Generation and screening of mouse models of ADRD with multiple genetic manipulations to model dementia with mixed brain pathologies

Abstract

AbstractBackgroundAlzheimer’s disease‐related dementias (ADRD) encompass a wide range of neurodegenerative diseases including Alzheimer’s disease, vascular dementia, frontotemporal dementia (FTD), Lewy body dementia (LBD), and mixed dementia [1‐4]. ADRDs are distinguished by the presence of pathologies including amyloid, tau, TDP‐43 inclusions, alpha‐synuclein aggregates, cerebral amyloid angiopathy, and/or hippocampal sclerosis [4‐9]. Consequently, the heterogeneity of ADRDs presents challenges for animal modeling of disease mechanisms. Our laboratory has demonstrated that genetic diversity in disease modeling is critical to recapitulate the molecular and cognitive features of AD [1,9, 10]. Here, we introduce multiple genetic manipulations to develop novel translational models of ADRD.MethodPrecision models of ADRD on multiple genetic backgrounds were generated via combinatorial CRISPR editing to knock‐in human disease‐causing mutations onto the C57BL/6J (B6) strain and crossed to either B6, DBA/2J (D2), FVB, or WSB to generate a set of 20 unique ADRD models (Fig.1). The effect of homozygous mutations were evaluated on the B6 background. Each model was assessed using a high‐capacity multi‐domain go/no‐go screen to prioritize candidate strains for future ADRD modeling of drug discovery, preclinical testing, and disease pathology.ResultAssays included frailty, open field, y‐maze, rotarod, and contextual fear conditioning. Models with one or more late‐onset behavioral deficits (12 mo) were a “go”; whereas, early behavioral deficits (6 and 9 mo), aggression, high attrition, and low fecundity and additional factors were considered unsuitable (“no‐go”). We identified several promising models of ADRD that exhibited late‐onset frailty and motor deficits as function of mutation burden and genetic background (e.g., App/Psen1/Tardbp/Mapt on the D2 background). The FVB background strain exhibited early frailty deficits (6 mo), and thus considered unsuitable (“no‐go”). The WSB background strain exhibited reserve across multiple frailty and behavioral assays up to 12 mo.ConclusionOur results demonstrate that combining ADRD mutations in genetically distinct backgrounds is a promising strategy to generate new mouse models that better model the human mid and late‐life onset of deficits associated with ADRD. The resulting model(s) will be translationally relevant and provide important insight into disease mechanisms for the future of ADRD research and drug discoveries.